Process for reacting salts of phenols with halo-alkanoic acid compounds



Patented Feb. 6,

PROCESS Foa REACTIG sALTs or PHENoLs WITH HALo-ALKANOIC ACID COMPOUNDS ley,

Cyanalnid-lCoinpany, New York, N. Y., a corporation of Maine No Drawing. Application August 17, 1948, Serial No. 44,804

mim (el: amai ,l 1y maure product have previously been ob ainied'jwhe'n itlias been attemptedV 'tof' Jprepare isopropylidene bis i (p-y phenokyacetic acid) by means of the above reaction or when similar reactions between other alkalinietal saltsof weakly acidicy organic compounds and: alkali' metal haloacetates have been attempted. We" believe that the poor yields of relatively impure product are'due tothe fact that thef'allali metal salt of the weakly acidic diga-nic conpund tncfls"v tolbe hydrolyzed', thus libratfree Ialkali in the reaction mixture Which, in turn, causes hydrlysis of the alkali metal haloacetate tothe corresponding glycollate. An obvious expedient to combat this loss of haloce'tate' by' hydrolysis and consequentreduction in yield and quality of the desired product `would seem to be the use of more than the stoichiom'etric quantity of haloacetate so that an excess would be present iny theireaction mixturetojreplace that portion of the haloacetate which is hydrolyzed. MHowever, We have `found that use gf *an-excessmo` haloacetate does not solve the Brme-1,11 @XQG t under certairlV Conditions., .and ,these lcertain ions `ce tutethe essence of the iiiocessof tl'pr'sent invntoni It is therefore an object of the present invention to provide al process for bringing about more ecient reaction between an alkali metal salt f a weakly acidic organic compound and. an organic compound containing a reactive halogen atom. i. l. MN. t a ,a

Another object of the present invention is. .12D provide a process iorincreasingltheproduction yield and quality .of tl1 e.reaction product citan alkali metal salt ofia weakly acidicorganic com.- pound' and rfa-n alkali metalfhaleacetate, It is further object of thevpre'sent inventiurl to so control theuse el.y anamountof alkali metal haloacetate in excess of thestoichiometric quantity required for reaction with an alkalimfltal salt of a weakly iacidicprvgegiic compound that increased yields df the desired reaction product are obtained.

More. SDeCfically, .anw obj ect otrthe present invention to provide" pofess fr tl prepration of isopropylideneebi's' (p-phenoxyacetic acid) 0f gdalllltylld hih ,yield l Theebove and ller Q'IO' bringing about reactwn between Sali Yof` a ,Wielslraidl 'Casarile4v ,C' t Gewerberaum ,fr tom attachedv to arf aliphatic @carbon aproclews's comprising the ste alkali metal' hydroiljdeA f ganicc'omp'ound con atom to the reac Wise ure. fr .L The invention Will VElie described great tail in conjunctionvvitnhV following sf'pecilic examples in which propd ons are given in parts by Weight. It shouldcbellunderstood that the examples are `merely illustrative, and it is not intended thatth -s"'cp'e0f the inve'ntl'oi 'be' liilted to the details therein set forth.

EXaMiLE 1 Pfil e 114,parts iof sopropylidene-d(1J-phenol) y(40.5

moll l .t 84;,5," partsff,` sou Y i000 parts oi w4 10Q para .idf ch 1 part ofp'otassiii l. Thibiroy de hasta sa (aliases 1)i `1s A A tle sodium "hydrgfglide in 500 parts of the water, the potassium fed de fluxing solution of the sodium salt of isopropylidenedi(pphenol). The reaction mixture is refluxed for three hours.

Y Y Part B 16.5 parts of sodium hydroxide, 97% (0.4 mol) 46.6 parts of sodium chloroacetate (0.4 mol) To the reaction mixture of Part A are added 10.3 parts (0.25 mol) of the sodium hydroxide and a solution of 25 parts of chloroacetic acid (0.26 mol) and 10.5 parts of sodium hydroxide (0.26 mol) in 125 parts of water, and the heating EXAl/IIPLE 4 Part A The procedure of Example 1 is repeated.

Part B Y 20.0 parts of sodium hydroxide (0.5 mol) 58.3 parts of sodium chloroacetate (0.5 mol) To the reaction mixture ofPart A are added the sodium hydroxide and sodium chloroacetate as in Example 2, but in portions of 0.25 mol of each, 0.15 mol of each, and 0.10 mol of each, re-

spectively. A 96.8% yield, on the same basis as i in the foregoing examples, of 93.2% isopropylidene bis-(p-phenoxyacetic acid) is obtained.

The results of Examples 1-4 inclusive are set out in the following tables:

propylidenedi(pphenol), of isopropylidene-bis- (p-phenoxyacetic acid) of 90.0% purity is obtained.

EXAlVIPLE 2 Part. A

y Thek procedure of Example 1 is followed.

Y Part B 13.7 parts of sodium hydroxide (0.33 mol) 38.4 parts of sodium chloroacetate (0.33 mol) Tov the Vreaction mixture of Part A are added vthe sodium hydroxide and sodium chloroacetate in three portions, 0.20 mol of each, 0.08 mol of each, and 0.05 mol of each, respectively. Each addition is followed by an hour of heating at reflux temperature. A 97.0 %Y yield, based on the weight of isopropylidene-di(p-phenol), of 90.5% pure isopropylidene bis-(p-phenoxyacetic acid) is obtained.

EXAMPLE 3 Part A The exact procedure of Example 1 is followed.

Part B 15.8 parts of sodium hydroxide (0.38 mol) 44.3 parts of sodium chloroacetate (0.38 mol) Part B Fils: addition Y second nddiiion Third addition NaOH, ClCHzCOONa, Reux. NaOH, ClOHaCOONa, Reflux, NaOH, ClCHzCOONa, Reux, mol mol hr. mol mol hr. mol molV hr.

0. 25 0.25 i 1 0.15 0-15 1 0. 0. 20 1 0. 0s 0. 0s 1 0. o5 0. o5 1 0. o. 25 1 0. 0s o. os 1 0. 05 0. 05 1 0.25 0. 25 .1 0,15 0.15 1 o. 10 0.10 1

under reilux is continued for an hour. 6.2 parts (0.15 mol) of sodium hydroxide and a neutral so- Example Perpent Perqent lution of 15.0 parts of chloroacetic acid and 6.5 Y Yle PuflW parts of sodium hydroxide in 75 parts of water V(0.16 mol of sodium chloroacetate) are then added, and reuxing is continued for an additional 0512 920 hour. A 96.5% by weight yield, based on the iso- 9&8 93-2 It will be apparent that successive Vretreatment 10 of the reaction mixture with excess sodium hydroxide and sodium chloroacetate results in an increase in the purity of the desired product after each addition. The increment of increase in purity upon successive retreatments becomes progressively smaller as the acid approaches 100% purity. Excess sodium hydroxide and sodium chloroacetate added in one portion either before or after the initial reilux of theoretical quantities of the principal reactants does not result in the. production of as pure isopropylidine bis(pphen oxyacetic acid or of as much isopropylidene bis(p phenoxyacetic acid) as when the excess is added in increments according to the process of the present invention.

While the invention is in no sense limited to our preferred embodiment, we prefer, for the practical preparation of isopropylidene bis(p phenoxyacetic acid) o f 90% or better purity, to use an excess of at least 50% of the amount of 6 sodium chloroacetate used in the initial reaction.

This excess is preferably added in three portions in the weight ratio o1"r 5:3 :2, but, as will be apparent from the precedingexamples, neither the amount of the excess nor the number of portions Y 5 in which it is added nor the weight ratio of the Example 4 represents the optimum in each'res. spect, namely, a 150% excess added in vthree por tions in thefratio of 51: 3:52.

yEXAMPLE 5 Part A A80.6 partsof 2,4dichlorophenol (0.5 mol) 4 212.5 partsoi sodium hydroxide,97% (1.02 mol) 270 parts of water 49.5 parts of monochloroacetic acid (0.52 mol) "6 parts ci potassium iodide The 2,4-dichlorophenol is dissolved in-asolution of 21 parts of the sodium hydroxide in 100 parts of the water. The monochloroacetic acid is neutralized with a solution of lf2-1.5 parts of the sodium hydroxide -in 270 parts of the water while maintaining the temperature below '50 C., and the neutralized solution is added to the prepared solution of the `sodium salt of lthe 2,4-dichlorophenol. The .potassium iodide is then added, and the resulting reaction mixture i's refluxed for'B'I/z hours.

Part B 13 parts of sodium hydroxide (0.33 mol) 450 partsof 'water 14 "parts of' monochloroacetic acid (0:15'mol) Fiveparts (0.13 mol) ofthe sodium hydroxide in A250 parts of the Water and a solution of '9 parts (0.1 mol)-of `the'rnonochloroacetic'acid and 4parts (0.1 mol) of the sodium hydroxide in 150 parts of the water are added to the reluxed reaction mixture of Part A, and refiuxing is .continued for y11/2 hours. Twofparts (0.05 mol) of thesodiumhydroxide and :a solution of 5 parts r 37 parts of 2-benzothiazolol (0.25 mol) 20.2 parts of sodiumhydroxide (0.5111101) 150 parts of water 25.5 parts (0.25 mol) of monochloroaceticiacld Asolutio'n of the '2 -benzothiazolol and 10.1part's of the sodium hydroxide inthe wateris heated nearly to reflux, 'whereupon an aqueous'neutral solution of the'chloroacetic acid andthe'remain'- ingsodium hydroxide is introduced. lThereactionm'ixture is then` reuxed for 3 hours.

Part B 8L4 parts ofA sodium hydroxide (0.2111101) 10.5jparts of chloroacetic lacid1 (0.11 4Tmol) "V258 parts '(0.07 mol) of the sodium' hydroxide and-fan' `aqueous solution of 2181pa`rts of thessol dium .hydroxide and T7 parts lof chloroacetic `acid (0.0?? mol `of sodium chloroacetate) are 4added vto the refluxed reaction mixture of Part A, .and reuxing is continued fog 1 hour. f1.4 .parts .of .the sodium hydroxide `and 'an aqueous solution of :3.5 parts of the ch'loroacetic .cid .and the remaining 1:4 parts of the sodium hydroxide are added, .and vreiluxing is again continued for 1 hour.

.'lhe reaction mixture .is nally claried with decolorizing carbon, i. e.,Darco, 4and the desired 2-'benzothiazolyloxyacetic acid is precipitated with sulfuric acid. A 66.7% yield of product melting at .174 C. lis obtained. i

The reactiondnvolved in this example maybe represented bythe -lfollowing chemical equation:

`2benzothiazolol Vused as the `starting material maybe prepared by oxidation of 2-benzothiazolethiol (well known by the trade name "Captax) with sodium hypochlorite in the presence of sodium hydroxide :to the corresponding sulfonic acid, as describedain U. S. Patent No. 2,018,813. The su1- ionic a'cidis readily'hydrolyzable to the ydesired hydroxy compound by heating with a mineral acid.

The processor the present invention is, of course, `'not limited Ato .thechloroacetic acid or alkali metal salt'thereof used in the specic examples. :Any organic compound containing an activehalogen atom attached to an aliphatic carbonfmay be used. Examples of such compounds' include'the'alkylene halohydrins such as ethylene chlorohydrin, glycerol dichlorohydrin, ethylene bromohydrin, etc., vhalogenated 'acids and esters thereof, particularly the .ii-'halogenated acids, such'as vbromoacetic acid, iodoacetic acid, uoroacetic acid, aand y-chlorbpropionic acids, achloroisobutyric acid, ethyl chloroacetate, phenyl asbromopropionatahenzyl uoroacetate, etc., saturatedfand unsaturated alkyl and aralkyl halides such as methyl chlorida'ethyl bromide, n-propyl iodide, `allyl chloride, benzyl chloride, etc., alkvylene rhalides -such .as :ethylene dichloride, 1,3- dibromopropane, 1,2-diiodopropane,,1,3-dich1oronbutane,etc.,fhalogenated acid A`amides such as chioroacetamide, bromopropionamide, N-methyliodoacetamide, N-benzyl-chloroacetamide, N- phenyl-echloroacetamide, N ',N -dimethyl-bromoacetamide, etc., halogenated nitriles such .as chloroacetonitrile,` -ibromopropionitrile, a-fluorobutyronitrile, etc., halogenated lethers such vas monochlorodimethyl ether, di(bromomethyl) ether, .iodomethyl -ethyl ether, mono-a-fluorodiethyl ether, etc., sulfur analogs of .the :above compounds such as .--chloroethyl .mercaptan, chlorothioacetic acid, ethyl bromothioacetate, chlorodithioacetic acid, methyl iodo'dithioacetate, mono'fluorodimethyl suliide, di-chloroethyl) sulfide, etc., andthe like.

`Similarly, the Vpresent invention'is not' limited t0` the Vusexf the "sodium salts of thereactants and to the addition in the iinal stages of sodium hydroxide, but the salts and hydroxides of other alkali metals may be used. Thus, for example,

' potassium hydroxide, lithium hydroxide and the like may be substituted for partorall `of the sodium hydroxide of the examples.

q The speciiic examples have given three representative types of weakly acidic organic com-` pounds to which the process of the Vpresent invention applies; in general, any weakly acidic organic compound which will form an alkali metal salt is useful in the process of the present invention. Compounds .of the phenolic or enolic type are generallypreferred, the process of the presentinvention therefore being applicable to the alkali metal salts of such compounds as phenol itself, alkyl substituted phenols such as cresol, xylenol, etc., halogenated phenols, cresols, xylenols and the like, such as 2chlorophenol, 4-bromophenol, 2-methyl-4-iluorophenol, 2,4-dibromo-6- ethylphenol, etc., polyhydric phenols such as resorcinol, phloroglucinol, -pyro-catechol, pyrogallol, etc., thiophenols such as thiophenol itself, the thiocresols, 2-chlorothiophenol, 2,4-dibromthiophenol, etc., nitrophenols such as nitrophenol itself, the nitrocresols, 2-chloro-4-nitrophenol, etc., 4,4'dihydroxydiphenyl and substitution products thereof such as 3,3'difluoro4,ll'dihy droxydiphenyl, etc., 2-mercaptobenzothiazole, mercaptothiazole, 4,4'dihydroxydiphenyl sulfone, acetoacetic acid esters such as ethyl acetoacetate, methyl alpha-bromoacetoacetate, etc.acetylace tone, acetoacetaldehyde, esters of malonic acid such as ethyl malonate, etc., mercaptoand hydroxy-oxazoles and imidazoles, and the like.

In the examples, the portions of excess organic compound containing a reactive halogen atom and alkali metal hydroxide are added together in balanced amounts at intervals separated by.

additional refluxing of the reaction mixture Providing that the excess reagents are added Vin balanced amounts, the order of addition of these` Y reagents is not critical and is determined only byV convenience of handling. Thus, if itis not particularly convenient to add the increments of both the halogen-containing material and the alkali metal hydroxide at intervals, the alkali metal hydroxide may be added at intervals with equivalent amounts of the halogen-containing compound added slowly and continuously to the reaction mixture. Alternatively, the halogen-containing material may be added at intervals and equivalent amounts of the alkali metal hydroxide introduced slowly and continuously. VFurthermore, it is possible to obtain satisfactory resultsv by simultaneously adding equivalent proportions 8 added 1n each step of the process foiiowing the initial reaction between stoichiometric quantities of the two ingredients is dependent upon the extent of hydrolysis occurring in the reaction of the step just preceding the addition in question. According1y,.the quantity added in any one step must be at least equivalent to the extent of hy- V drolysis in the preceding step. For example, in

of alkali -metal hydroxide and theorganic com'Y I pound containing an active halogen atom slowly and continuously at `controlled rates. Thus, it is quite apparent that the order or manner of addition of the excess reactants has no eiect on either the yield or purity of the desired reaction product so long as the total excess quantity of neither of the reactants is added all at once. i

It has been stated that excess quantities of gen-containing` compound which Ytakes place under the influence of alkali metal hydroxide liberated by hydrolysis of the alkali metal saltY ofv the weakly acidic organic compound. Therefore, the' amount of excess of reagents which must be the case ofthe reaction of Examples 1-4 inclusive, the initial reaction mixture, afterVV reflux, contains about 60% of the sodium salt of the desired bis acid and about 40% of the sodium salt of an acid having Vthe formula The rst addition thereafter of sodium hydroxide and sodium chloroacetate must therefore represent at least a 207% excess over the original quantities. 4After refiuxing, the reaction mixture contains 84% bis acid and 16% of the mono acid; ac# cordingly, at least an 8% excess of reagents must be added in the next step. And so the amount of excess is determined for each subsequent step. While use of the minimum excess results Aina satisfactory product within the scope of the pres; entirivention, i. e., nearly theoretical yieldof bis acid of at least %v purity as borne out by Ex'- arnple 2 in which the minimum quantities were used, we prefer using slightly more than the minimum excess. There is no theoretical upper -limit to the amount of excess over and above the mini-v mum; practical and commercial considerations control.` VThe upper limit is determined empirically in each case and is represented by the point at which a greater excess effects little or no in crease in purity. The purity may, of course, be readily determined at eachstep by titration or any other suitable means; l

The invention is not limited to the addition of the excess reagents in any particular number'of increments. Here again the number of portions necessary will depend at least in part on the extent of undesirable hydrolysis occurring in the main' reaction. In order to obtain an optimum degree of purity in good yield, the excess reagents must be added in at least two portions, they are preferably added in three portions, and they may be added in any number of additional portions.

Obviously, the greater the number of steps in which the three reagents are added, the greater the purity of the product obtained up to a certain point, but in practical commercial operation a balance, of course, must be sought between the degrec of purity necessary and the cost of additional time and handling occasioned by an unnecessarily large number of additions.V

.The process of the present invention may be' carried out :in aqueous or alcoholic media.

The principal advantage` of the present inven' tion resides in the fact that by its applcation pure reaction products of alkali metal salts of weakly acidic organic compounds and organic compounds containing active halogen atoms may be prepared in high yield. The commercial and practical advantages of a process giving high yields of desired product are, of course, obvious. In many cases, an impure product of one kind or another serves a particular purpose just as Well as the same product in a highly purified form, and in such cases the process of the present invention would be of no great commercial value. There arelmany cases, however, where the purity of a,

product is extremely critical, and in such cases the process of the present invention is most advantageous. For example, the isopropylidene bis pphenoxyacetic acid) of Examples 1 4 may be used in the prepa-ration of alkyd resins. A large amount of the monobasic acid is produced if merely stoichiometric quantities of 'the sodium salt of isopropylidene di(p-phenol) and sodium chloroacetate are used or if an excess of the chloroacetate is added in one portion either before or after the initial reaction. Dimcult and costly purification steps are required to separate the desired dibasic acid from admixture with the monobasic acid. rihis monobasic acid is an undesirable impurity because its presence destroys the desirable properties of resins prepared by condensation with a polyhydric alcohol.

2-benzothiazolyloxyacetic acid is useful as a plant growth regulant; Zebenzothiazolol has no such property. If the steps of the present process are not applied in the preparation cf the former by reaction or" the latter with sodium chloroacetate, the product will contain as an impurity a iairly large amount of the 2-benzothiazolol Which not only lowers the yield of the desired product having plant growth regulant properties, but also its eiectiveness per unit Weight.

It is another advantage of the present invention that by adding excess reactants in small increments, the amounts of each increment being determined by the extent of hydrolysis of the alkali metal salt of the halogen-containing organic compound in the reaction stage just preceding the addition, the production of a product of extremely high purity in very high yield with the smallest amount of excess reactants is made possible.

A further advantage of the present invention is that its process makes unnecessary any time-consuming and expensive purications of reaction products in cases where a product of high purity is either desirable or necessary.

We claim:

A process which comprises heating together stoichiometric quantities of an alkali metal salt of isopropylidene di(pphenol) and chloroacetic acid for a suiiicient time to bring about an initial reaction between the two ingredients, introducing into the reaction mixture alkali metal hydroxide and additional chloroacetic acid in at least two portions, the amount of each portion depending upon the extent to which the chloroacetic acid has been hydrolyzed in the previous reaction stage, and heating the reaction mixture after each of said introductions.

HAROLD M. DAY. MARGARET H. BRADLEY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,083,482 Steindori et al June 8, 1937 2,158,064 Carothers May 16, 1939 2,252,666 Reii et al. Aug. 12, 1941 2,322,761 Lontz June 29, 1943 2,370,256 Niederl Feb. 27, 1945 2,375,138 Salvin et al May 1, 1945 2,375,885 Babcock May 15, 1945 2,444,594 Day et al July 6, 1948 FOREIGN PATENTS Number Country Date 573,476 Great Britain Nov. 22, 1945 573,510 Great Britain Nov. 23, 1945 592,827 Great Britain Sept. 30, 1947 OTHER REFERENCES Pokorny: J. Am. Chem. Soc., vo-l. 63, p. 1768 (1941). Y

Berhenke et al.: 1nd. Eng. Chem., vol. 38, pp. 544-546 (1946). 

